Production of some antibody isotypes

FIGURE 9-15 Development of TH1 cells. IL-12 produced by dendritic cells and macrophages in response to microbes, including intracellular microbes, and IFN-y produced by NK cells (all part of the early innate immune response to the microbes) activate the transcription factors T-bet, STAT1, and STAT4, which stimulate the differentiation of naive CD4+ T cells to the TH1 subset. IFN-y produced by the TH1 cells amplifies this response and inhibits the development of TH2 and TH17 cells.

T cells engaging CD40 on the APCs and stimulating IL-12 secretion.

IFN-y and IL-12 stimulate TH1 differentiation by activating the transcription factors T-bet, STAT1, and STAT4 (see Fig. 9-15). T-bet, a member of the T-box family of transcription factors, is considered to be the master regulator of TH1 differentiation. T-bet expression is induced in naive CD4+ T cells in response to antigen and IFN-y. IFN-y activates the transcription factor STAT1, which in turn stimulates expression of T-bet. T-bet then promotes

IFN-y production through a combination of direct transcriptional activation of the IFN-y gene and by inducing chromatin remodeling of the IFN-y locus. The ability of IFN-y to stimulate T-bet expression and the ability of T-bet to enhance IFN-y transcription set up a positive amplification loop that drives differentiation of T cells toward the TH1 phenotype. IL-12 contributes to TH1 commitment by binding to receptors on antigen-stimulated CD4+ T cells and activating the transcription factor STAT4, which further enhances IFN-y production. Mice deficient in IL-12, IL-12 receptor, T-bet, or STAT4 cannot mount effective TH1 responses to infections, and humans with genetic deficiencies in the IL-12R signaling pathway have impaired responses to infections with several kinds of intracellular bacteria.

Th2 Differentiation

Th2 differentiation is stimulated by the cytokine IL-4 and occurs in response to helminths and allergens (Fig. 9-16). Helminths and allergens cause chronic T cell stimulation, often without the strong innate immune responses that are required for TH1 differentiation. Thus, TH2 cells may develop in response to microbes and antigens that cause persistent or repeated T cell stimulation without much inflammation or the production of pro-inflammatory cytokines that drive TH1 and TH17 responses. The differentiation of antigen-stimulated T cells to the TH2 subset is dependent on IL-4, which raises an interesting question: Because differentiated TH2 cells are the major source of IL-4 during immune responses to protein antigens, where does the IL-4 come from before TH2 cells develop? In some situations, such as helminthic infections, IL-4 produced by mast cells and, possibly, other cell populations, such as basophils recruited into lymphoid organs and eosinophils, may contribute to TH2 development. Another possibility is that antigen-stimulated CD4+ T cells secrete small amounts of IL-4 from their initial activation. If the antigen is persistent and present at high concentrations, the local concentration of IL-4 gradually increases. If the antigen also does not trigger inflammation with attendant IL-12 production, the result is increasing differentiation of T cells to the TH2 subset. Once TH2 cells have developed, the IL-4 they produce serves to amplify the reaction and inhibits the development of TH1 and TH17 cells.

IL-4 stimulates TH2 development by activating the transcription factor STAT6, and STAT6, together with TCR signals, induces expression of GATA-3 (see Fig. 9-16). GATA-3 is a transcription factor that acts as a master regulator of TH2 differentiation, enhancing expression of the TH2 cytokine genes IL-4, IL-5, and IL-13, which are located in the same genetic locus. GATA-3 works by directly interacting with the promoters of these genes and also by causing chromatin remodeling, which opens up the locus for accessibility to other transcription factors. This is similar to the way in which T-bet influences IFN-y expression. GATA-3 functions to stably commit differentiating cells toward the TH2 phenotype, enhancing its own expression through a positive feedback loop. Furthermore, GATA-3 blocks TH1 differentiation by inhibiting expression of the signaling chain of the IL-12 receptor. Knockout mice lacking IL-4, STAT6, or GATA-3 are deficient in TH2 responses.

Helminths

Naive T cell

Helminths

Naive T cell

Effector functions: IgE production - Eosinophil activation IL-131 ^^ ^Mucosal secretions

FIGURE 9-16 Development of TH2 cells. IL-4 produced by activated T cells themselves or by mast cells and eosinophils, especially in response to helminths, activates the transcription factors GATA-3 and STAT6, which stimulate the differentiation of naive CD4+ T cells to the Th2 subset. IL-4 produced by the TH2 cells amplifies this response and inhibits the development of TH1 and TH17 cells.

Th17 Differentiation

The development of TH17 cells is stimulated by proinflammatory cytokines produced in response to bacteria and fungi (Fig. 9-17). Various bacteria and fungi act on dendritic cells and stimulate the production of cytokines including IL-6, IL-1, and IL-23. Engagement of the lectin-like receptor Dectin-1 on dendritic cells by fungal products is a signal for the production of these cytokines. The combination of cytokines that drive TH17 cell development may be produced not only in response to particular

Bacteria, fungi

Naive T cell

Bacteria, fungi

Naive T cell

Isotype And Immunology

FIGURE 9-17 Development of TH17 cells. IL-1 and IL-6 produced by APCs and transforming growth factor-p (TGF-p) produced by various cells activate the transcription factors RORyt and STAT3, which stimulate the differentiation of naive CD4+ T cells to the TH17 subset. IL-23, which is also produced by APCs, especially in response to fungi, stabilizes the TH17 cells. TGF-p may promote TH17 responses indirectly by suppressing TH1 and TH2 cells, both of which inhibit TH17 differentiation (not shown in the figure). IL-21 produced by the TH17 cells amplifies this response.

FIGURE 9-17 Development of TH17 cells. IL-1 and IL-6 produced by APCs and transforming growth factor-p (TGF-p) produced by various cells activate the transcription factors RORyt and STAT3, which stimulate the differentiation of naive CD4+ T cells to the TH17 subset. IL-23, which is also produced by APCs, especially in response to fungi, stabilizes the TH17 cells. TGF-p may promote TH17 responses indirectly by suppressing TH1 and TH2 cells, both of which inhibit TH17 differentiation (not shown in the figure). IL-21 produced by the TH17 cells amplifies this response.

microbes, such as fungi, but also when cells infected with various bacteria and fungi undergo apoptosis and are ingested by dendritic cells. IL-23 may be more important for the proliferation and maintenance of TH17 cells than for their induction. TH17 differentiation is inhibited by IFN-y and IL-4; therefore, strong TH1 and TH2 responses tend to suppress TH17 development. A surprising aspect of Th17 differentiation is that TGF-p, which is produced by many cell types and is an anti-inflammatory cytokine

(see Chapter 14), promotes the development of proin-flammatory TH17 cells when other mediators of inflammation, such as IL-6 or IL-1, are present. Some experimental results indicate that TGF-p does not directly stimulate TH17 development but is a potent suppressor of Th1 and TH2 differentiation and thus removes the inhibitory effect of these two subsets and allows the TH17 response to develop under the influence of IL-6 or IL-1. According to this idea, the action of TGF-p in promoting Th17 responses is indirect. TH17 cells produce IL-21, which may further enhance their development, providing an amplification mechanism.

The development of TH17 cells is dependent on the transcription factors RORyt and STAT3 (see Fig. 9-17). TGF-p and the inflammatory cytokines, mainly IL-6 and IL-1, work cooperatively to induce the production of RORyt, a transcription factor that is a member of the retinoic acid receptor family. RORyt is a T cell-restricted protein encoded by the RORC gene, so sometimes the protein may be referred to as RORc. The inflammatory cytokines, notably IL-6, activate the transcription factor STAT3, which functions with RORyt to drive the TH17 response. Mutations in the gene encoding STAT3 are the cause of a rare human immune deficiency disease called Job's syndrome because patients present with multiple bacterial and fungal abscesses of the skin, resembling the biblical punishments visited on Job. These patients have defective TH17 responses.

Th17 cells appear to be especially abundant in mucosal tissues, particularly of the gastrointestinal tract, suggesting that the tissue environment influences the generation of this subset, perhaps by providing high local concentrations of TGF-p and other cytokines. This observation also suggests that TH17 cells may be especially important in combating intestinal infections and in the development of intestinal inflammation. The development of TH17 cells in the gastrointestinal tract is also dependent on the local microbial population.

The functions of differentiated effector cells of the CD4+ lineage are mediated by surface molecules, primarily CD40 ligand, and by secreted cytokines. We will describe the cytokines produced by differentiated CD4+ effector cells and their functions in Chapter 10.

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